PJSS Vol. 68, No.

1, January-March, 2013 PHILIPPINE JOURNAL OF1

PJSS SURGICAL SPECIALTIES

Update on Certain Aspects of the Evidence-based Clinical Practice Guidelines on

Thyroid Nodules (Focused on the Diagnosis and Management of Well-Differentiated
Thyroid Cancer)

Ida Marie Tabangay-Lim, M.D., F.P.C.S.; Arlene T. Fajardo, M.D., F.P.C.S.;

Marwin Emerson V. Matic, M.D. and Alfred Philip O. de Dios, M.D., F.P.C.S. for the Philippine Academy
of Head and Neck Surgeons, Inc.

Fernando L. Lopez, M.D., F.P.C.S. and Nilo C. De los Santos, M.D., F.P.C.S. for the Philippine Society
of General Surgeons

Ma. Luisa D. Aquino, M.D., F.P.C.S.; Ma. Cheryl L. Cucueco, M.D., F.P.C.S.;
Leonardo O. Ona III, M.D., F.P.C.S. and Jose Modesto B. Abellera III, M.D., F.P.C.S. for the
Philippine College of Surgeons Committee on Surgical Research

The Philippine College of Surgeons (PCS) through its This project was funded solely by the PCS Foundation.
Committee on Surgical Research, in cooperation with The Technical Working Group (TWG), composed of
the Philippine Society of General Surgeons (PSGS) and fellows from the PCS, PAHNSI and PSGS was formed
the Philippine Academy of Head and Neck Surgery, Inc. last May 2012.
(PAHNSI) published the Evidence-based Clinical
Practice Guideline on Thyroid Nodules in 2008 (PJSS Technical Working Group:
Vol 63 No. 3). This guideline covers the comprehensive
management of thyroid nodules -both benign and For PAHNSI:
malignant. After five years, the PCS through its Alfred Philip O. de Dios, MD
Committee on Cancer and Committee on Surgical Arlene T. Fajardo, MD
Research, again in cooperation with the PAHNSI and Marwin Emerson V. Matic, MD
the PSGS worked on updating its guidelines particularly Ida Marie Tabangay-Lim, MD
those pertaining to the management of thyroid cancer,
which is among the top ten cancers in the Philippines. For PCS:
This update focuses on the diagnostic and therapeutic Ma. Luisa D. Aquino, MD
aspects of the management of well-differentiated thyroid Jose Modesto B. Abellera III, MD
cancer including postoperative surveillance. It is based Cheryl L. Cucueco, MD
on the most recent available scientific evidence and the Leonardo O. Ona III, MD
views of local experts. It is intended to guide surgeons
(fellows, resident trainees) and general physicians For PSGS:
involved in the management of thyroid cancer and Fernando L. Lopez, MD
practicing in the Philippines. Nilo C. de los Santos, MD

1
2 PJSS Vol. 68, No. 1, January-March, 2013

The research questions from the 2008 guidelines Category C Recommendation caused real
were reviewed and modified as needed, focusing on disagreements among members of
well-differentiated thyroid cancer. Important new issues the panel
to update the working list of research questions were
discussed and developed by the members of the TWG
and the PCS Committee on Surgical Research. These Members of the Expert Panel:
include the role of thyroid ultrasound in detecting
malignancy and the role of central node dissection in the 1. Alejandro C. Dizon, MD
management of well-differentiated thyroid cancer. 2. Jose Macario V. Faylona, MD
The search of the available literature included 3. Ramon S. Inso, MD
publications from 2007 onwards using the same 4. George G. Lim, MD
electronic database used in the 2008 PCS EBCPG: 5. Ramoncito C. Magnaye, MD
Pubmed(Medline) plus Cochrane database and manual 6. Maximo B. Nadala, MD
search of the following libraries: UST,UP and De La 7. Enrico P. Ragaza, MD
Salle Health Sciences. The search was guided by the 8. Rhoel de Leon, MD
clinical research questions using MESH terms as 9. Mark R. Kho, MD
applicable . All existing clinical practice guidelines on 10. Daniel L. de la Paz, MD
thyroid cancer were likewise searched, and the 11. Edgardo R. Cortez, MD
references used in these guidelines were reviewed if 12. Rodney B. Dofitas, MD
applicable. A total number of 50 articles were used as 13. Joselito F. David, MD
reference for this update. 14. Juan P. Sanchez Jr., MD
The evidences were appraised, and the initial 15. Ray I. Sarmiento, MD
draft of recommendations was prepared together with 16. Jose Roberto V. Claridad, MD
the PCS Committee on Surgical Research last October 17. Rowen Yolo, MD
13, 2012. The group agreed to apply the Levels of 18. Jonas Y. Santiago, MD
Evidence of the Oxford Centre for Evidence-Based 19. Sjoberg A. Kho, MD
Medicine, 2011 for the new recommendations.(See 20. Bien J. Matawaran, MD
Appendix A) 21. Ruben L. Carreon, MD
The initial draft was presented to a multidisciplinary 22. Lino Santiago S. Pabillo, MD
panel of experts and members of the PCS Board of
Regents during the PCS Annual Clinical Congress on
December 5, 2012, for some revisions, and for the List of Clinical Questions:
strength of the recommendations.
The final draft was presented in a public forum 1. What is the appropriate diagnostic work-up in a patient
during the Philippine Society of General Surgeons with thyroid nodule ?
Annual Meeting on August 1, 2013 held at the SMX 1.1 What is the role of thyroid function tests ( TSH, T3,
Convention Hall. T4, FT4)?
1.2 What is the role of ultrasonography ?
Categories of Recommendations 1.2.1 Who should undergo ultrasonography?
1.2.2 What are the indications for doing ultrasound
Category A At least 75 percent consensus by expert guided fine needle aspiration biopsy?
panel present 1.3 What is the role of radioisotope scan?
1.4 What is the role of fine needle biopsy (FNAC)?
Category B Recommendation somewhat 1.5 What is the role of frozen section in the
controversial and did not meet consensus intraoperative diagnosis of thyroid nodule?
Update on Certain Aspects of the EBCPG on Thyroid Nodules
2. What is the recommended treatment for well-
differentiated thyroid cancer (WDTC)?
2.1 What is the recommended surgical procedure for
the treatment of WDTC?
2.2 What is the role of central node dissection in the
management of patients with well-differentiated
thyroid cancer in improving overall and disease-
free survival?
2.2.1 What is the role of therapeutic central node
dissection?
2.2.2 What is the role of prophylactic central node
dissection?
2.3 What is the role of radioactive iodine remnant
ablation therapy in the treatment of WDTC?
2.4 What is the role of completion thyroidectomy in the
treatment of WDTC?
2.5 What is the role of external beam radiation in the
treatment of WDTC?
2.6 What is the role of TSH suppression therapy in the
treatment of WDTC?
3. What is the recommended postoperative surveillance
for patients with WDTC?
3.1 What is the role of thyroglobulin assay for
postoperative surveillance in patients with WDTC?
3.2 What is the role of TSH for postoperative
surveillance in patients with WDTC?
3.3 What is the role of ultrasonography for postoperative
surveillance in patients with WDTC?
3.4 What is the role of whole body scan for postoperative
surveillance in patients with WDTC?
Recommendations with no new evidence:
After search of the literature was done, no new
evidence was found regarding the following research
questions of the PCS EBCPG on Thyroid Nodules
published in 2008, hence their recommendations remain
the same:
1. What is the appropriate diagnostic work up for a patient
with a thyroid nodule?
1.1 Role of thyroid function tests: TSH, T3, T4
1.3 Role of radioisotope scan in the diagnosis of thyroid
nodule
3
1.4 Role of fine needle biopsy (FNAC) in the diagnosis
of thyroid nodule
1.5 Role of frozen section in the intraoperative diagnosis
of a thyroid nodule.
2. What is the recommended treatment for well-
differentiated thyroid cancer?
2.4 Role of completion thyroidectomy in the treatment
of WDTC
2.5 Role of external beam radiation in the treatment of
WDTC
3. What is the recommended postoperative surveillance
for patients with WDTC?
3.3 What is the role of ultrasonography for postoperative
surveillance in patients with WDTC?
3.4 Role of whole body scan in the postoperative
surveillance of patients with WDTC?
Recommendations with updated evidence:
1. What is the appropriate diagnostic work-up in a patient
with thyroid nodule?
1.2 What is the role of ultrasonography in the diagnosis
of thyroid nodule?
1.2.1 Who should undergo ultrasonography?
1.2.2 What are the indications for doing ultrasound
guided fine needle aspiration biopsy?
2. What is the recommended treatment for well-
differentiated thyroid cancer?
2.1 What is the recommended surgical procedure for
well differentiated thyroid cancer?
2.2 What is the role of central node dissection in the
management of patients with well-differentiated
thyroid cancer in improving overall and disease free
survival?
2.2.1 What is the role of therapeutic central node
dissection?
2.2.2 What is the role of prophylactic central
compartment dissection?
2.3 What is the role of radioactive iodine remnant
ablation therapy in the treatment of WDTC?
2.4 What is the role of TSH suppression therapy in the
treatment of WDTC?
4 PJSS Vol. 68, No. 1, January-March, 2013
3. What is the recommended postoperative surveillance
for patients with WDTC?
3.1 What is the role of thyroglobulin assay in the
postoperative surveillance of patients with WDTC?
3.2 What is the role of TSH in the postoperative
surveillance of patients with WDTC?
Recommendations
1. What is the appropriate diagnostic work-up in a patient
with thyroid nodule?
1.2 What is the role of ultrasonography in the diagnosis of
thyroid nodule?
1.2.1 Who should undergo ultrasonography?
Thyroid ultrasound is not recommended as a screening
test for the general population.
It is recommended for the following:
1. Evaluation of the patient with nodular goiter.
2. Those with adenopathy suggestive of a malignant
lesion.
3. Screening of High-risk patients (patients with history of
familial thyroid cancer, previous diagnosis of MEN2,
childhood cervical irradiation).
Level 5, Category B
Summary of Evidence
High-resolution ultrasound is the most sensitive test
available to detect thyroid lesions, measure their
dimensions accurately, identify their structure and
evaluate diffuse changes in the thyroid gland. Ultrasound
can identify thyroid nodules that have been missed on
physical examination, isotope scanning and other imaging
techniques. This study, however, should not be performed
on an otherwise normal thyroid gland nor used as a
substitute for a physical examination. The role of
ultrasound as a screening test for thyroid nodules is
limited.1 Due to the high prevalence of thyroid nodules
and the high survival rate and good prognosis, the
consensus made by the AACE is that a screening test for
thyroid malignancy is not justified.2
In all patients with palpable thyroid nodules or MNG,
ultrasound should be performed to accomplish the
following: help with the diagnosis in difficult cases (as in
Hashimoto's thyroiditis), look for coincidental thyroid
nodules, detect ultrasound features suggestive of
malignant growth and select the lesions to be
recommended for fine-needle aspiration (FNA) biopsy.
The physical finding of adenopathy suspicious for
malignant involvement in the anterior or lateral neck
compartments warrants ultrasound examination of the
lymph nodes and thyroid gland because of the risk of a
lymph node metastatic lesion from an otherwise
unrecognized papillary microcarcinoma.
Ultrasound should be performed in all patients with
a history of familial thyroid cancer (Familial Medullary
Thyroid Carcinoma and Familial Non-medullary Thyroid
Carcinoma), Multiple Endocrine Neoplasia type 2, or
childhood cervical irradiation, even if palpation yields
normal findings.
Familial non-medullary thyroid carcinoma (NMTC)
refers to those neoplasms originating from the thyroid
epithelial cell, and includes papillary thyroid carcinoma
(PTC), follicular thyroid carcinoma (FTC), anaplastic
thyroid carcinoma, and insular thyroid carcinoma.
In patients with non-specific symptoms (cervical
pain, dysphagia, persistent cough, voice changes),
ultrasound evaluation of the thyroid gland should be
performed only on the basis of findings on physical
examination and the results of appropriate imaging and
laboratory tests.
Standardized ultrasound reporting criteria should be
followed, indicating position, shape, size, margins, content,
echogenic pattern, and, whenever possible, the vascular
pattern of the nodule.2 For multiple nodules, detail the
nodule(s) bearing the ultrasound characteristics
associated with malignancy (hypoechoic pattern and/or
irregular margins, a more-tall-than-wide shape,
microcalcifications, or chaotic intranodular vascular
spots).3 rather than describing the largest ("dominant")
nodule.
Nodules with malignant potential should be identified,
and fine needle aspiration biopsy should be suggested to
the patient.
Update on Certain Aspects of the EBCPG on Thyroid Nodules
References
1. Won-Jin Moon, Jung Hwan Baek, So Kyung Jung, et al.
Ultrasonography and the ultrasound-based management of thyroid
nodules: Consensus statement and recommendations. Korean J
Radiol 2011; 12(1): 1-14.
2. Gharib H, Papini E, Valcavi R, et al. American Association of
Clinical Endocrinologists and Associazione Medici Endocrinologi
Medical guidelines for clinical practice for the diagnosis and
management of thyroid nodules. Endocr Pract 2010; 16 (1).
3. Lopez FL, Ampil IDE, Aquino MLD, et al. The PCS-PSGS-
PAHNSI evidence-based clinical practice guidelines on thyroid
nodules. PJSS 2008; 63(3): ____.
4. Cooper DS, Doherty GM, Haugen BR, et al. Revised American
Thyroid Association management guidelines for patients with
thyroid nodules and differentiated thyroid cancer. Thyroid [Erratum
(2010)20:674-675] 2009; 19: 1167-214.
1.2.2. What are the indications for doing ultrasound
guided fine needle aspiration biopsy?
Ultrasound-guided fine needle aspiration biopsy is
indicated for:
1. Multinodular goiter with suspicious ultrasound
findings for malignancy
2. Complex (mixed cystic-solid) appearing nodule/s
3. Posteriorly located nodule/s
4. Ultrasound detected solitary nodule with malignant
findings
5. Nodules greater than 1cm with indeterminate
ultrasound findings
6. Nodules that are less than 1cm with indeterminate
ultrasound findings which increase in size in a 6-18
months interval (more than a 50%change in volume
or a 20% increase in at least two nodule dimensions
with a minimal increase of 2 mm in solid nodules
or in the solid portion of mixed cystic-solid nodules)
Level 3, Category A
Summary of Evidence
With the advent of technology advancement, the
application of ultrasound-guided fine needle aspiration
biopsy has been deemed as both reasonable and
5
appropriate as part of the diagnostic armamentarium of
a general surgeon in the management of a possible
thyroid malignancy.
Studies abroad have demonstrated that it is accurate
and efficient in determining malignancy in a thyroid
nodule.1,2,3
Locally, a retrospective study by Young, et al.3 in
2011 involving 2,239 nodules from 1,737 patients who
underwent ultrasound guided FNAB showed that the
procedure had a sensitivity of 70.3%, a specificity of
92.8%, a positive predictive value of 76.5%, a negative
predictive value of 90.4%, and an accuracy rate of
87.2%.
The use of ultrasound becomes more apparent with
its ability to detect characteristics that are suspicious for
malignancy at its smallest/earliest dimension. In a
retrospective study by Sahin, et al.1 in 2006 involving 145
patients, they were able to demonstrate the ability of the
ultrasound to diagnose microcarcinoma (less than 1
centimeter in diameter) with a sensitivity of 96.3%, a
specificity of 71.2%, a negative predictive value of
44.8%, a positive predictive value of 98.8% and an
accuracy rate of 76.1%.
However, studies by Kim4 and Mazaferri5 have
recommended not to biopsy nodules smaller than 5 mm
in size because of a high rate of false positive US findings
as well as a high rate of inadequate cytology.
A retrospective study by Kim, et al. in 20094
involving 438 thyroid nodules that have been divided into
groups A (<5mm), B (>5mm ≤ 10mm), and C (>10mm),
demonstrated a decrease in sensitivity (85.7% vs 97.7%
vs 100%), negative predictive value (94.9% vs 100% vs
100%), and accuracy (96.1% vs 99.1% vs 99.4%) in
group A compared to the other groups.
Mazzaferri5 cites that doing a needle biopsy in such
small nodules evokes major patient anxiety and is likely
to yield cytology that is insufficient for diagnosis,
especially when done by those lacking in technical
experience. Their study recommends periodic ultrasound
examination as likely to be a better option for such
patients since their small nodules may spontaneously
disappear or fail to grow over time.
However, in a retrospective study by Ga Ram Kim,
et al.6, of 1,238 nodules with cytology and/or histologic
confirmation which analyzed the ultrasound
6 PJSS Vol. 68, No. 1, January-March, 2013
characteristics of large (> 10mm) versus small nodules
(< 10mm) , they found that there is a difference in the
sonographic characteristics predictive of malignancy
between small and big nodules. On multivariate analysis,
the following sonographic features were shown to be
independent factors for PTC in large nodules :irregular
margin (OR = 37.788, P < 0.001), microcalcifications
(OR = 17.799, P <0.001), microlobulated margin (OR
=10.385, P < 0.001), and no vascularity (OR = 5.975,
P< 0.001) . On the other hand, the following were noted
to be independent factors in small lesions : irregular
margin (OR = 7.185, P <0.001), microlobulated margin
(OR = 5.952, P < 0.001), microcalcifications (OR =
3.722, P<0.001), marked hypoechogenicity (OR = 2.873,
P = 0.004), and taller than wide shape (OR = 2.698,
P<0.001. Hence, the need to do FNAC should be based
on sonographic features and not on nodule size alone.
Woon-Jin Moon, et al.7 recommend that if a nodule
has indeterminate findings on US and is larger than 1 cm
in diameter, ultrasound guided FNA should be performed
due to the fact that the possibility of malignancy cannot
be ruled out. If a nodule has indeterminate findings and
it is 1 cm or less in size, a follow-up US would be
appropriate, 6-18 months following the initial.5 A growing
nodule (more than a 50% change in volume or a 20%
increase in at least two nodule dimensions with a minimal
increase of 2 mm in solid nodules or in the solid portion
of mixed cystic-solid nodules) necessitates a USFNA.5
When multiple nodules are found on US, not all of the
nodules have to be biopsied. The risk of malignancy for
patients with multiple thyroid nodules is not greatly
different from that for patients with a single thyroid
nodule. According to the ATA guideline8, in the presence
of two or more nodules 1-1.5 cm or more in size, a FNA
biopsy is recommended for nodules with suspicious US
findings. If none of the nodules has suspicious US
findings, then FNA should be done for the largest one.
References
1. Sahin M, Sengul A, Berki Z, Tutuncu NB, Guvener ND. Ultrasound-
guided fine-needle aspiration biopsy and ultrasonographic features
of infracentimetric nodules in patients with nodular goiter:
correlation with pathological findings. Endocr Pathol 2006; 17:
67-74.
2. Cai XJ, Valiyaparambath N, Nixon P, Waghorn A, Giles T,
Helliwell T. Ultrasound guided fine needle aspiration cytology in
the diagnosis and management of thyroid nodules. Cytopathology
2006; 17.
3 Young JK, Lumapas CG, Mirasol R. Sonographically guided fine-
needle aspiration biopsy of thyroid nodules: Correlation between
cytologic and histopathologic finding. Phil J Int Med 2011; 49(1).
4. Kim DW, Lee EJ, Kim SH, et al. Ultrasound-guided fine-needle
aspiration biopsy of thyroid nodules: comparison in efficacy
according to nodule size. Thyroid 2009; 19: 27-31.
5. Mazzaferri EL, Sipos J. Should all patients with subcentimeter
thyroid nodules undergo fine-needle aspiration biopsy and
preoperative neck ultrasonography to define the extent of tumor
invasion? Thyroid 2008; 18: 597-602.
6. Ga Ram Kim, Myung Hyun Kim, Hee Jung Moon, et al. Sonographic
characteristitcs suggesting papillary thyroid carcinoma according
to nodule size. Ann Surg Oncol 2013; 20: 906-13.
7. Won-Jin Moon, Jung Hwan Baek, So Kyung Jung, et al.
Ultrasonography and the ultrasound-based management of thyroid
nodules: Consensus statement and recommendations. Korean J
Radiol 2011; 12(1): 1-14.
8. Cooper DS, Doherty GM, Haugen BR, et al. Revised American
Thyroid Association management guidelines for patients with
thyroid nodules and differentiated thyroid cancer. Thyroid [Erratum
(2010) 20: 674-675] 2009; 19: 1167-214.
2. What is the recommended treatment for well
differentiated thyroid cancer (WDTC) that will improve
overall and/or disease free survival?
2.1 What is the recommended surgical procedure for
well differentiated thyroid cancer that will improve
overall and/or disease free survival?
The recommended surgical procedure for the
treatment of WDTC is near-total or total thyroidectomy.
A lobectomy with isthmusectomy may be considered
for selected low risk T1 and T2 tumors
Level 3, Category A
Summary of Evidence
The general slow progression of well-differentiated
carcinoma has limited the production of randomized
controlled trials with regards to the extent of surgery of
well-differentiated thyroid cancer. Review of cohort
Update on Certain Aspects of the EBCPG on Thyroid Nodules 7

studies has produced much controversy which is yet survival (OS) and cause-specific survival rates (CSS).
unresolved. However, performing lobectomy only produced higher
In the PCS Thyroid Guidelines of 2008, the OS and CSS but they were not statistically different
recommendation regarding total or near total (Figures 2 & 3).
thyroidectomy as the surgical procedure of choice was
based mainly on the works of Udelsman and
Mazzaferri. 1,2,3
For papillary and follicular thyroid cancers,
Mazzaferri, et al.2 reported that lobectomy alone resulted
in a 5%-10% recurrence rate in the opposite lobe, a high
tumor recurrence rate, and a high (11%) incidence of
pulmonary metastases. They stated that bilateral
thyroidectomy and I131 ablation is justified by the high
recurrence rates in patients with cervical LN metastasis
and multicentric tumors. The 20-year rates for local
recurrence and nodal metastasis after lobectomy were
14 and 19 percent, respectively, significantly higher
(P=0.0001) than the 2 and 6 percent rates seen after
bilateral thyroid resection. Patients treated with total or
near-total thyroidectomy plus I131 ablation and L-thyroxine
had significantly fewer recurrences and distant
recurrences than those treated with any other combination Total+T4 58/419 31/318 6/240 3/205 3/178 4/132 7/80 1/25

(Figure 1). However, some have stated that the increase

in recurrence rate and decrease in survival were found
Subtotal+T4
Subtotal+T4+Rai
Total+T4+Rai
40/350
10/67
38/449
17/270
2/40
10/282
9/211
1/27
2/203
4/165
1/18
6/168
7/141
0/14
1/135
2/93
0/8
2/92
3/53
0/7
1/55
0/24
}
0/5 <0.05
}
0/19
<0.001

to have an independent effect on survival on multivariate Figure 1. Recurrence rates following thyroid surgery and hormonal
analysis. Mazzaferri, et al. also chose to exclude patients suppression +/- RAI.
Source: Mazzaferri and Kloos. Current approaches to primary therapy
with lesions under 1.5cm from the analysis. 4
for papillary and follicular thyroid cancer. J Clin Endocrinol Metabol
After total thyroidectomy, serial serum thyroglobulin 2001; 86: 4.
measurements become a useful marker for recurrence.
Postoperative iodine 131 (I131) scans can be performed
to diagnose recurrent or metastatic disease, and I131 can
be used to ablate residual thyroid bed uptake or distant
metastases. In addition, the total dose of I131 required for
ablative therapy is far less following total thyroidectomy.
Importantly, the local recurrence rate following total
thyroidectomy is decreased, and the re-operative thyroid
surgery with its inherently increased risks is minimized.
Recent cohort studies however, suggest the possibility
of performing a less than total thyroidectomy for selected
patients. With the increase in performing ultrasound as
a diagnostic test for thyroid lesions, small thyroid cancer
lesions can be easily detected. Barney, et al. 4 conducted
a 19-year study of 23,605 subjects with well-differentiated
cancer. They concluded that performing total Figure 2. Overall survival by extent of surgery. NOS, not otherwise
thyroidectomy produced improved 10-year overall specified (Barney,2011).
8 PJSS Vol. 68, No. 1, January-March, 2013

This was supported by a study of Nixon, et al. 5 in

Figure 3. Cause-specific survival by extent of surgery. NOS, not
otherwise specified.
2012 of 889 patients of Memorial Sloan Kettering Cancer
Center with T1 and T2 tumors with a follow-up of 99
months( Table 1). Univariate analysis showed that that
there was no significant difference in the 10-year overall
survival according to extent of surgery. There was also
no difference in local ( 0% for both )and regional
recurrence ( 0% vs 0.8 % P = .96) between total
thyroidectomy and subtotal thyroidectomy groups. Age
over 45 and male gender were the independent predictors
of poor overall survival. Based on the results of the
above studies, thyroid lobectomy with isthmusectomy
may be considered as a safe alternative to total
thyroidectomy for T1 and T2 well-differentiated tumors
(Table 2).
Another study by Mendelsohn, et al.6 was conducted
among 22,724 patients with papillary thyroid carcinoma.

Table 1. Patient characteristics, tumor characteristics and outcomes stratified by surgical group (Nixon, 2012).

Variable Lobectomy Total thyroidectomy P value

n = 361 n = 528
n (%) n (%)
Age
<45 yr 185 (54) 230 (44) .002
>45 yr 166 (46) 298 (56)
Gender
Male 82 (23) 106 (20) .345
Female 279 (77) 422 (80)
pT stage
pT1 249 (69) 388 (73) .143
pT2 112 (31) 140 (27)
RAI
No 360 (99.7) 333 (63) <.001
Yes 1 (0.3) 195 (27)
Pathology
Papillary Ca 310 (86) 490 (93) <.001
Follicular Ca 36 (10) 16 (3)
Hurthle cell Ca 15 (4) 22 (4)
10-yr local recurrence 0 (0) 0 (0) 1
10-yr neck recurrence 0 (0) 5 (0.8) .96
10-yr distant recurrence 0 (0) 5 (3) .05
10-yr deaths of any cause 18 (7) 27 (9) .64
10-yr disease-specific deaths 0 (0) 1 (1.5) .245
RAI, Radioiodine ablation
Update on Certain Aspects of the EBCPG on Thyroid Nodules
Table 2. 10 year overall survival for lobectomy and total thyroidectomy
groups stratified by pT,pT size and risk group. (Nixon, 2012)
Among these, 5,964 patients underwent only lobectomy.
Even by performing subgroup analysis for tumors 1 cm
or larger, they found no significant difference in the
overall survival and disease-specific survival between
the groups of lobectomy versus thyroidectomy (P = .05
for OS and P = .09 for DSS) (Table 4).
Despite recent data supporting performing a less
than total thyroidectomy for small thyroid carcinomas,
caution must be exercised and proper selection of such
Table 3. Cox proportional HRs for overall and disease specific survival (Mendelsohn,2010).
Table 4. Recurrences according to treatment carried out for each classification system(Hurtado-Lopez,et al. 2011)
9
candidates is needed since it was found in a retrospective
medical record review done in Canada that Filipino
patients experienced a thyroid cancer recurrence rate of
25% compared with 9.5% for non-Filipino patients (OR,
3.20; 95% CI, 1.23-7.49; P = .004). 7
A retrospective study by Pellegriti, et al.8 found that
approximately 20 percent of small (< 1.5%) papillary
thyroid cancer had extra thyroid invasion and/or bilateral
foci which might have been overlooked in most previous
studies where microcarcinoma patients where treated with
lobectomy. This is important because multifocal thyroid
cancers have a relapse rate higher than unifocal cancers,
which is also true for microcarcinomas (8.6% vs. 1.2%).
The study showed that although small papillary
cancers have a favorable outcome, it might present with
signs of aggressiveness including multifocality (30%),
LN metastases (30%), vascular invasion (4.7%), and
even distant metastases (2.7%). Moreover, 77 (25.7%)
of their patients showed evidence of persisting/relapsing
disease during the follow-up period of 12.2 to 252.4
10
months (median of 45.2). This study recommended
near-total or total thyroidectomy as the first choice
surgical treatment.
Studies done in other countries recently have
supported the need for total thyroidectomy for low risk
papillary thyroid cancer. An observational study by
Hurtado, et al.9 involving 128 low risk papillary thyroid
cases with 10 year follow up showed higher recurrence
rates for those who have undergone hemithyroidectomy
only as shown on Table 4. The recurrences were mainly
regional metastases.
In another study in Romania by Varcus10, which
retrospectively reviewed 228 patients who had completion
thyroidectomy after histological confirmation of thyroid
cancer in the ipsilateral lobe. Only one patient with
cancer < 1cm in ipsilateral lobe had malignant lesions in
the contralateral lobe ( 4/7%). However, in patients with
tumors > 1cm, the frequency of malignant lesions in the
contralateral lobe was between 42.8% and 47.6%. This
again supports the recommendation of doing a total
thyroidectomy for tumors > 1cm.
Minimal invasive and endoscopic techniques for
thyroidectomy have already been performed in our
country. More studies are desired before any guidelines
can be recommended for such procedures.
References
1. Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary
thyroid carcinoma. World J Surg 1996; 20: 88-93.
2. Mazzaferri EL, Kloos RT. Clinical Review 128: Current approaches
to primary therapy for papillary and follicular thyroid cancer. J
Clin Endocrinol Metab 2001; 86: 1447-1463.
3. Lopez FL, Ampil IDE, Aquino MLD, etal. The PCS-PSGS-PAHNSI
evidence-based clinical practice guidelines on thyroid nodules. Phil
J Surg Spec 2008; 63(3).
4. Barney BM, Hitchcock YJ, Sharma P, Shrieve DC, Tward JD.
Overall and cause-specific survival for patients undergoing
lobectomy, near-total, or total thyroidectomy for differentiated
thyroid cancer. Head Neck 2011; 35 (5): 645-9.
5. Nixon IJ, Ganly I, Patel SG, Palmer FL, Whitcher MM, Tuttle RM,
Shaha A, Shah JP. Thyroid lobectomy for treatment of well
differentiated intrathyroid malignancy. Surgery 2012; 151 (4):
571-9.
6. Mendelsohn AH, Elashoff DA, Abemayor E, St John MA. Surgery
for papillary thyroid carcinoma: is lobectomy enough? Arch
Otolaryngol Head Neck Surg 2010; 136(11): 1055-61.
7. Kus LH, Shah M, Eski S, Walfish PG, Freeman JL. Thyroid cancer
outcomes in Filipino patients. Arch Otolaryngol Head Neck Surg
2010; 136(2): 138-42.
PJSS Vol. 68, No. 1, January-March, 2013
8. Pellegriti G, Scollo C, Lumera G, Regalbuto C, Vigneri R, Belfiore
A. Clinical behavior and outcome of papillary thyroid cancers
smaller than 1.5 cm in diameter: Study of 299 cases. J Clin
Endocrinol Metab 2004; 89(8): 3713-3720.
9. Hurtado-López LM, Melchor-Ruan J, Basurto-Kuba E, Montes de
Oca-Durán ER, Pulido-Cejudo A, Athié-Gutiérrez C. Low-risk
papillary thyroid cancer recurrence in patients treated with total
thyroidectomy and adjuvant therapy vs. patients treated with
partial thyroidectomy. Cirujiya y cirujanos. 2011; 79 (2): 118-25.
10. Varcus F, Bordos D, Cornianu M, Nicolicea A, Coman A, Lazar
F. Thyroid cancer--the malignant lesions in the contralateral lobe.
Chirurgia (Bucur). 2011; 106 (6): 765-8.
2.2 What is the role of central node dissection in the
management of patients with well differentiated
thyroid cancer in improving overall and disease free
survival?
2.2.1 What is the role of therapeutic central
compartment lymph node dissection
(CLND)?
Therapeutic CLND is recommended for those with
clinically palpable or ultrasonographically detected
nodes.
Level 2, Category A
Summary of Evidence
Clinically evident lymph node involvement is a well-
established indication for therapeutic dissection. The
removal of involved cervical lymph nodes is part of loco-
regional control of the disease. Two systematic reviews1,2
showed higher rates of persistent and recurrent disease
on follow-up for patients with lymph node metastases.
Compartment-oriented lymph node dissection is shown
to result to lower recurrences as compared to 'berry
picking'. There are no clear evidences for its impact on
over-all survival.
References
1. Hughes DT, Doherty GM. Central neck dissection for papillary
thyroid cancer. Cancer Control 2011; 18(2): 83-8.
2. Sakorafas GH, Sampanis D, Safioleas M. Cervical lymph node
dissection in papillary thyroid cancer: current trends, persisting
controversies and unclarified uncertainties. Surg Oncol 2010; 19:
e57-e70.
Update on Certain Aspects of the EBCPG on Thyroid Nodules
2.2.2 What is the role of prophylactic central
compartment lymph node dissection?
Prophylactic central node dissection is not
recommended because it does not improve overall and
disease free survival.
Level 2, Category A
Summary of Evidence
Fifteen journal articles (1 prospective cohort, 11
retrospective cohorts, 2 systematic reviews and 1 meta-
analysis) reported on the incidence of metastasis in the
harvested nodes among patients who underwent
prophylactic central lymph node dissection (CLND), or
on the recurrence rate or disease-free survival against
complication rates of the added procedure. Also noted
was the effect of the procedure on the parameters used
for surveillance.
The incidence of micrometastases in central
compartment nodes ranges from as low as 45.8%1 to as
high as 60.9%.2 Most micrometastases can be found in
the pretracheal (40%) and ipsilateral (34.5%) group of
nodes while the contralateral group showed an incidence
of 17.4%.2
Several studies showed no significant difference in
the recurrence rate between patients undergoing total
thyroidectomy with CLND and those undergoing a total
thyroidectomy only.2,3 But the best evidence comes
from two systematic reviews4,5 which concluded that
prophylactic CLND does not improve cancer survival
and that there is no significant difference in recurrence
rate in patients having total thyroidectomy and
prophylactic CLND versus total thyroidectomy alone.
As to the complication rates, majority of studies
showed an increased incidence of transient hypocalcemia
and parathyroid autotransplantation among patients who
underwent an additional CLND to their surgical treatment.
The incidence of transient hypocalcemia ranges from
18%-51.9% for bilateral CLND, 20.5%-36.1% for
unilateral CLND and 0.5%-27.7% for those without
CLND.3,6,7,8,9,10 Wong4 gave the same conclusion and
Chisholm11 gave a risk difference of 0.13 translating into
one incident of temporary hypocalcemia for every 7.7
11
CLNDs performed. Moreover, White, et al.12 showed
an increased incidence of permanent hypocalcemia and
recurrent laryngeal nerve paralysis in patients undergoing
total thyroidectomy and CLND. They reported a further
increased risk of hypocalcemia and unintentional nerve
injury, if the CLND was done as a second procedure.
Giordano10 showed a higher incidence of transient
hypocalcemia if a bilateral CLND instead of just an
ipsilateral CLND was performed (51.9% vs 36.1%). It
should be noted that most of these studies employed
patients whose procedures were performed by endocrine
surgeons.
References
1. Chae BJ, Jung CK, Lim DJ, et al. Performing contralateral central
lymph node dissection in papillary thyroid carcinoma: a decision
approach. Thyroid 2011; 21(8): 873-7. Epub 2011 Jul 11
2. Wada N, Duh QY, Sugino K, et al. Lymph node metastasis from
259 papillary thyroid microcarcinomas: frequency, pattern of
occurrence and recurrence, and optimal strategy for neck dissection.
Ann Surg 2003; 237: 399-407.
3. Shen WT, Ogawa L, Ruan D, et al. Central neck lymph node
dissection for papillary thyroid cancer. Arch Surg 2010; 145(3):
272-5.
4. Wong KP and Lang HH. The role of prophylactic central neck
dissection in differentiated thyroid carcinoma: Issues and
controversies. J Oncol 2011; Article ID 127929
5. Sakorafas GH, Sampanis D, Safioleas M. Cervical lymph node
dissection in papillary thyroid cancer: current trends, persisting
controversies and unclarified uncertainties. Surg Oncol 2010;
19:e57-e70.
6. Palestini, et al. Is central neck dissection a safe procedure in the
tx of papillary thyroid cancer? Our experience. Langenbecks
Arch Surg 2008; 393: 693-8.
7. Lee YS, Kim SW, Kim SW, et al. Extent of routine central lymph
node dissection with small papillary thyroid carcinoma. World J
Surg 2007; 31: 1954-9.
8. Lang BH, Wong KP, Wan KY, Lo CY.Impact of routine unilateral
central neck dissection on preablative and postablative stimulated
thyroglobulin levels after total thyroidectomy in papillary thyroid
cancer. Ann Surg Oncol 2012; 19: 60-7.
9. Sywak M, Cornford L, Roach P, Stalberg P, Sidhu S, Delbridge L.
Routine ipsilateral level VI lymphadenectomy reduces
postoperative thyroglobulin levels in papillary thyroid cancer.
Surgery 2006; 140: 1000-7.
10. Giordano D, Valcavi R, Thompson GB, et al.Complications of
central neck dissection in patients with papillary thyroid carcinoma:
results of a study on 1087 patients and review of literature.
Thyroid. 2012; 22(9): 911-7.
11. Chisholm EJ, Kulinskaya E, Tolley NS. Systematic review and
meta-analysis of the adverse effects of thyroidectomy combined
with central neck dissection as comopared with thyroidectomy
alone. Laryngoscope 2009; 119: 1135-9.
12 PJSS Vol. 68, No. 1, January-March, 2013

12. White ML, Gauger PG, Doherty GM. Central lymph node dissection For low risk patients who underwent total
in differentiated thyroid cancer. World J Surg 2007; 31: 895-904.
13. Yoo D, Ajmal S, Gowda S, Machan J, Monchik J, Mazzaglia P. Level
thyroidectomy, there is no benefit in giving RAI remnant
VI lymph node dissection does not decrease radioiodine uptake in ablation therapy in terms of improving disease-free
patients undergoing radioiodine ablation for differentiated thyroid survival.
cancer. World J Surg 2012; 36(6): 1255-61.
14. Alvarado R, Sywak MS, Delbridge L, Sidhu SB. Surgery. Central
lymph node dissection as a secondary procedure for papillary Level I, Category A
thyroid cancer: Is there added morbidity? 2009; 145: 514-8.
15. So YK, Seo MY, Son YI. Prophylactic central lymph node Summary of Evidence
dissection for clinically node-negative papillary thyroid
microcarcinoma: Influence on serum thyroglobulin level,
recurrence rate and postoperative complications. Surgery 2012; A meta-analysis by Sawka, et al in 20041 showed
151: 192-8. that RAI ablation may be beneficial in decreasing
recurrence of WDTC. Although no randomized controlled
studies were obtained, 23 studies were included out of
2.3 What is the role of radioactive iodine remnant 267 full-text papers independently reviewed. Pooled
ablation therapy in improving overall and disease- analysis showed a statistically significant treatment effect
free survival? of ablation for the following 10-year outcomes:
Locoregional recurrence (RR of 0.31); and distant
Radioactive iodine remnant ablation therapy is metastases (absolute risk reduction of 3%) (Figures 1 &
beneficial in decreasing locoregional recurrence and 2).
distant metastases.
Radioiodine Ablation Control RR Weight RR
Study n/N n/N (95% CI Random) % (95% CI Random)
01 Papillary Cancer
Hong Kong (P) 2002 24/444 24/143 71.1 0.32 (0.19, 0.56)
Zurich (Sig.I, II: P) 1/43 1/54 2.7 1.28 (0.08, 19.50)
Subtotal (95%CI) 25/487 25/197 73.8 0.34 (0.20, 0.57)
Test for heterogeneity chi-square = 0.92 df = p = 0.34
Test for overall effect z = 4.05 p = 0.00005

02 Papillary and Follicular Cancer

U of Toronto (P, F) 5/121 13/99 20.4 0.31 (0.12, 0.85)

03 Follicular Cancer
Hong Kong (F) 2002 2/123 2/12 6.8 0.18 (0.02, 0.63)
x Lahey (capsule: F, H) 0/20 0/72 0.0 Not Estimatable
x Zurich (Min inv. F) 0/17 0/9
100.0 Not Estimatable
Total (95% CI) 32/768 40/389
Test for heterogeneity chi-square = 2.51 df = 3 p = 0.47
Test for overall effect z = 5.10 p<0.00001

• • • •
.001 .02 50 1000
Favours treatment Favours control

Figure 1. Random effects pooled estimate of RR reduction of RAI ablation on development of locoregional recurrence at 10 yr. n, Number
of events; N, size of population studied; P, papillary; F, follicular; H, Hurthle cell; Stg I, II, stage I or II; Min inv, minimally invasive; capsule,
only capsular invasion.
Source: Sawka A, Thephamongkhol K, Brouwers M, Thabane L, Browman G, Gerstein H. Clinical Review 170: A systematic review and meta-
analysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab 2004; 89(8):
3668-76.
Update on Certain Aspects of the EBCPG on Thyroid Nodules 13

However, Sawka, et al.2 in 2008, published an updated
systematic review on the effectiveness of RAI in well-
differentiated thyroid cancer.2 They stated that the benefit
of RAI is unclear among low risk patients who underwent
total or near-total thyroidectomy and are receiving thyroid
hormone suppressive therapy. A similar conclusion was
reported by another systematic review by Sacks, et al. in
2010.3 Majority of very low-risk and low-risk patients
who underwent post-operative RAI ablation did not
demonstrate increased survival or disease-free survival.
This is further supported by a randomized phase 3
trial done by Schlumberger, et al.4 in 2012. A total of 752
patients were enrolled and 92% of the cases had papillary
cancer. Their results showed that a low dose of post-
operative RAI ablation may be sufficient for low risk
cancer to lessen the complications brought about by
radiation exposure.
However, it is important to consider that for the
subsequent follow-up of patients who did not receive
post-operative RAI ablation, monitoring through the use
of serum Tg levels will be complicated.
The decision to give RAI ablation must be
individualized, based on the risk profile of the patient, as
well as patient and physician preference, while balancing
the risks and benefits of such therapy.
References
1. Sawka A, Thephamongkhol K, Brouwers M, Thabane L, Browman
G, Gerstein H. Clinical Review 170: A systematic review and meta-
analysis of the effectiveness of radioactive iodine remnant ablation
for well-differentiated thyroid cancer. J Clin Endocrinol Metab
2004; 89(8): 3668-76.

Radioiodine Ablation Control RR Weight RR

Study n/N n/N (95% CI Random) % (95% CI Random)

01 Papillary Cancer
Hong Kong (P) 2002 4 / 444 5 / 143 21.1 -0.03 (-0.08, 0.01)
Zurich (Stg. IU: P) 0 / 43 0 / 54 12.9 0.00 (0.04, 0.04)
Subtotal (95% CI) 4 / 487 5 / 197 34.0 -0.22 (0.04, 0.01)
Test for heterogeneity chi-square = 1.13 df =1 p = 0.28
Test for overall effect z = 1.17 p = 0.2

02 Papillary and Follicular Cancer

Ohio, USAF 2001 2 / 230 34 / 769 80.3 -0.03 (0.05, -0.02)

03 Follicular Cancer
Hong Kong (F) 2002 9 / 123 1 / 12 0.8 0.01 (-0.17, 0.15)
Lahey (capsule: F, ) 0 / 20 0 / 72 4.5 0.00 (-0.07, 0.07)
Zurich (Min inv. F) 0 / 17 1 /9 0.4 -0.11 (-0.07, 0.05)
Subtotal (95% CI) 9 / 180 2 / 93 5.7 -0.01 (-0.07, 0.05)
Test for heterogeneity chi-square = 0.90 df = 2 p = 0.54
Test for overall effect z = 0.29 p = 0.8

Total (95% CI) 15 / 877 41 / 1079 100.0 -0.03 (-0.04, -0.01)

Test for heterogeneity chi-square = 3.51 df = 5 p = 0.62
Test for overall effect z = 3.83 p = 0.0003

.001 .02 50 1000

Favours treatment Favours control
Figure 2. Random effects model examining the RD of RAI ablation on development of distant metastases at 10 yr. n, Number of events; N,
size of population studied; P, papillary; F, follicular; H, Hurthle cell; Stg I, II, stage I or II; Min inv, minimally invasive; capsule, only capsular
invasion; node+, including cervical lymphadenopathy.

Source: Sawka A, Thephamongkhol K, Brouwers M, Thabane L, Browman G, Gerstein H. Clinical Review 170: A systematic review and
metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab 2004;
89(8): 3668-76.
14 PJSS Vol. 68, No. 1, January-March, 2013

Figure 3. Pooled analysis examining risk difference for any thyroid cancer recurrence after radioactive iodine ablation ( Sawka 2008).

Figure 4. Pooled analysis examining the risk difference for loco-regional thyroid cancer recurrence after radioactive iodine remnant
ablation ( Sawka 2008).
Update on Certain Aspects of the EBCPG on Thyroid Nodules
2. Sawka AM, Brierley JD, Tsang RW, Thabane L, Rotstein L, Gafni
A, Straus S, Goldstein DP. An updated systematic review and
commentary examining the effectiveness of radioactive iodine
remnant ablation in well-differentiated thyroid cancer. Endocrinol
Metab Clin North Am 2008; 37(2): 457-80.
3. Sacks W, Fung CH, Chang JT, Waxman A, Braunstein GD. The
effectiveness of radioactive iodine for treatment of low-risk
thyroid cancer: a systematic analysis of the peer-reviewed literature
from 1966 to April 2008. Thyroid 2010; 20(11): 1235-45.
4. Schlumberger M, Catargi B, Borget I, et al. Strategies of radioiodine
ablation in patients with low-risk thyroid cancer. N Engl J Med
2012; 366(18): 1663-73.
2.6 What is the role of TSH suppression therapy in the
treatment of WDTC?
Thyroid hormone suppression therapy following a
risk stratified approach may reduce recurrence and
improve thyroid cancer-specific mortality rates and
overall survival rate among high risk patients or those
with stage III or IV disease.
Considering the adverse effects of TSH suppression
therapy, there is no significant benefit for low risk
patients especially for those with no residual or active
disease.
Level 2, Category A
Specific Recommendations:
For high risk and intermediate risk* thyroid cancer
patients , initial TSH suppression to below 0.1mU/L is
recommended for 3 - 5 years.
For low risk* thyroid cancer patients who either
received or did not receive remnant ablation, maintenance
of the TSH at or slightly below the lower limit of normal
(0.1-0.5 mU/L) is adequate so as to minimize the toxic
effects of aggressive thyroid suppression therapy.
(*According to the Risk Stratification for Recurrence, ATA 2009)
Level 5, Category A
Summary of Evidence
Thyroid hormone suppression therapy after surgery
with or without remnant ablation is an important part of
15
the multimodal treatment of thyroid cancer. Theoretically,
it is effective in stopping the growth of microscopic
thyroid cancer cells or residual thyroid cancer. 1
A prospective cohort (n=2938) which stratified
patients into low risk ( Stage I and II by NTCTCSG
criteria) or high risk (stage III and IV) compared overall
survival, disease-specific, and disease-free survival
according to treatment received including degree of
thyroid hormone suppression therapy. Aggressive thyroid
hormone suppression therapy was found to be associated
with longer overall survival among high risk patients.
Moderate thyroid hormone suppression therapy predicted
improved over-all survival in stage II patients. There
was no impact of thyroid hormone suppression therapy
among stage I patients.2
In a retrospective cohort of patients with metastatic
differentiated carcinoma who received initial treatment
and follow up in a single institution, DTC-specific
survival was found to be significantly better in patients
with a median TSH level of ≤ 0.1 mU/l (median survival
15.8 years) than those with a non-suppressed TSH level
(median survival 7.1 years; p<0.001). However,
suppressing TSH further ( ≤ 0.03 mU/l ; p= 0.24) did not
result in improved survival.3
A randomized controlled trial comparing patients
with papillary thyroid cancer who received TSH
suppression therapy with those who did not, showed that
disease-free survival was not inferior by more than 10%
among those whose did not receive TSH suppression.4
There are still ongoing discussions on the duration of
suppression therapy. According to the current guidelines
by ESMO 5, low-risk patients who are disease-free after
initial treatment may be shifted from suppressive to
replacement LT4 therapy, with the goal of maintaining
serum TSH level within the low normal range. However,
for patients determined as high risk at the time of
diagnosis but has been determined to be disease free on
their first follow up after initial treatment, it is advisable
to maintain them on suppressive doses of LT4 therapy
(TSH < 0.1 uUI/ml) for 3-5 years because the risk of
relapse in this subset of patients on long-term follow-up
may still be significant.
Biondi and Cooper6 proposed initial serum TSH
targets based on the ATA risk stratification for cancer
recurrence and progression7, as well as the patients' risk
16 PJSS Vol. 68, No. 1, January-March, 2013

from adverse effects of LT4. The following must be
taken into account: the age of the patient, and the
presence of preexisting cardiovascular and skeletal risk
factors that might predispose to the development of long-
term adverse cardiovascular or skeletal outcomes,
particularly increased heart rate and left ventricular
mass, atrial fibrillation, and osteoporosis. Using this
scheme, nine potential patient categories can be defined,
with differing TSH targets for both initial and long-term
L-T4 therapy (Tables 1 & 2).

Table 1. Suggested initial thyrotropin targets in thyroid cancer patients according to risk assessment (Biondi, 2010).

Risk of cancer recurrence and progression

Risk from T4 therapy High Intermediate Low

High <0.1mU/L a 0.1mU/La 0.5-1mU/L

Intermediate <0.1mU/L b <0.1mU/Lb 0.5-1mU/L

Low <0.1mU/L <0.1mU/L 0.1-0.5mU/L

a With high risk from L-T4: consider cardiovascular drugs, calcium, vitamin D, and antiresorptive drugs.
B With intermediate risk from L-T4 and high or intermediate risk of tumor progression: consider b-adrenergic blocking drugs, calcium,
and vitamin D.
L-T4, levothyroxine.

Table 2. Suggested thyrotropin targets in thyroid cancer patients according to risk assessment during follow-up (Biondi, 2010).

Risk of cancer recurrence and progression

Risk from T4 therapy High Intermediate Low

High <0.1mU/L persistent or 0.5-1mU/L if disease 1-2mU/L

metastatic disease; free for 5-10 years, then
0.1-0.5mU/L if disease 1-2mU/L
free for 5-10 years (a)

Intermediate <0.1mU/L persistent 0.1-0.5mU/L if disease 1-2mU/L

or metastatic disease b; free for 5-10 years, then
0.1-0.5mU/L if disease 1-2mU/L
free for 5-10 years

Low <0.1mU/L persistent or 0.1-0.5mU/L if disease 0.3-2mU/L

metastatic disease c; free for 5-10 years, then
0.1-0.5mU/L if disease 0.3-2mU/L
free for 5-10 years

a With high risk from L-T4 with persistent=metastatic disease: TSH suppression should be adapted to the clinical situation.
b With intermediate risk from L-T4 with persistent=metastatic disease: consider cardiovascular drugs, calcium, and vitamin D.
c With low risk from L-T4 with persistent=metastatic disease: periodic cardiovascular and BMD assessment.
Update on Certain Aspects of the EBCPG on Thyroid Nodules
References
1. Brabant G. Thyrotropin suppressive therapy in thyroid carcinoma:
what are the targets? J Clin Endocrinol Metab 2008; 93: 1167-9.
2. Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with
differentiated thyroid carcinoma following initial therapy. Thyroid
2006; 16: 1229-42.
3. Diessl S, Holzberger B, Mäder U, et al. Impact of moderate vs
stringent TSH suppression on survival in advanced differentiated
thyroid carcinoma. Clin Endocrinol (Oxf). 2012; 76(4):586-92.
doi: 10.1111/j.1365-2265.2011.04272.x. PubMed PMID:
22059804.
4. Sugitani I, Fujimoto Y. Does postoperative thyrotropin suppression
therapy truly decrease recurrence in papillary thyroid carcinoma?
A randomized controlled trial. J Clin Endocrinol Metab 2010;
95(10): 4576-83. Epub 2010 Jul 21. PubMed PMID: 20660039.
5. Pacini1 F, Castagna MG, Brilli L and Pentheroudakis G. On behalf
of the ESMO Guidelines Working Group on Thyroid Cancer:
ESMO clinical practice guidelines for diagnosis, treatment and
follow-up. Ann Oncol 2010; 21 (Supplement 5): v214-9.
6. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus
the risks of adverse effects in differentiated thyroid cancer.
Thyroid 2010; 20(2):135-46.
7. Cooper DS, Doherty GM,Haugen BR,et al. Task force on Thyroid
Nodules and Differentiated Thyroid Cancer. Revised American
Thyroid Association management guidelines for patients with
thyroid nodules and differentiated thyroid cancer. The American
Thyroid Association (ATA) Guidelines. Thyroid 2009; 19(11).
3. What is the recommended postoperative surveillance
for patients with well-differentiated thyroid cancer?
Postoperative surveillance with the goal of detecting
recurrence among disease free patients and progression
of disease among those with residual disease can be
accomplished by utilizing serum thyroglobulin, serum
TSH, thyroid ultrasound, with or without whole body
scan, according to the patient's risk stratification for
recurrence and/or death.
Level 5, Category A
Summary of Evidence
After initial surgery and remnant ablation, the risk
for recurrence and mortality in patients with well
differentiated thyroid cancer should be determined
based on the ATA 2009 risk stratification into low,
intermediate, or high risk, and the AJCC TNM staging
17
respectively (Table 1).1 This can be used as a guide in
determining the need and frequency of doing surveillance
tests.
The diagnostic tests employed for post operative
surveillance of patients with WDTC should have a high
negative predictive value, so that patients who are
unlikely to experience disease recurrence could be
identified, hence, less aggressive management strategies
which are more cost effective and safe can be used .
Similarly, patients with a higher risk of recurrence
should be monitored more aggressively for early
detection of recurrent disease, which offers the best
opportunity for effective treatment.2
Table 1. ATA initial risk of recurrence classification (ATA 2009):
Low-risk patients have the following characteristics:
1. no local or distant metastases;
2. complete removal of macroscopic tumor
3. there is no tumor invasion of locoregional tissues or structures nor
vascular invasion
4. the tumor does not have aggressive histology (e.g., tall cell, insular,
columnar cell carcinoma)
5. and, if 131I is given, there is no 131I uptake outside the thyroid
bed on the first posttreatment whole-body RAI scan (RxWBS)
Intermediate-risk patients have any of the
following:
1. microscopic invasion of tumor into the perithyroidal soft
tissues at initial surgery;
2. cervical lymph node metastases or
3. I131 I uptake outside the thyroid bed on the RxWBS
done after thyroid remnant ablation
4. tumor with aggressive histology or vascular invasion
High-risk patients have:
1. macroscopic tumor invasion,
2. incomplete tumor resection,
3. distant metastases, and possibly
4. thyroglobulinemia out of proportion to what is seen on
the posttreatment scan
18
References
1. Tala H, Tuttle RM. Contemporary post surgical management of
differentiated thyroid carcinoma. Clin Oncol (R Coll Radiol).
2010; 22(6):419-29. Epub 2010 Jun 1.
2. Cooper DS, Doherty GM,Haugen BR,et al. Task force on Thyroid
Nodules and Differentiated Thyroid Cancer. Revised American
Thyroid Association management guidelines for patients with
thyroid nodules and differentiated thyroid cancer. The American
Thyroid Association (ATA) Guidelines. Thyroid 2009; 19(11).
3.1 What is the role of thyroglobulin assay for
postoperative surveillance in patients with well
differentiated thyroid cancer in detecting
recurrence or progression of disease?
Serum thyroglobulin monitoring is essential in the
follow up of patients with well differentiated thyroid
cancer who underwent total thyroidectomy and
radioactive iodine ablation to help detect recurrence or
progression of disease
Level 2, Category A
Specific Recommendations:
1. To ensure an accurate and reliable measurement of
serum Tg, an immunometric assay calibrated against
the CRM- 457 international standard is recommended.
If this is not possible, measurements in individual patients
over time should be performed in the same laboratory
and using the same assay. Quantitative determination
of thyroglobulin antibodies should be likewise be done
with every measurement of serum Tg.
Level 2, Category A
2. For low risk who underwent less than total thyroidectomy
or total thyroidectomy without remnant ablation: periodic
TSH-suppressed Tg and cervical ultrasound, followed
by TSH-stimulated serum Tg measurements if the
TSH- suppressed Tg testing is undetectable should be
done. The change (increase) in Tg values over time
should be used as a basis to work up a patient for
possible progression or recurrence of disease rather
PJSS Vol. 68, No. 1, January-March, 2013
than specific cut off levels of Tg (whether on TSH
suppression or stimulation).
Level 4, Category A
3. For low risk DTC who underwent total thyroidectomy
with remnant ablation with negative ultrasound and
undetectable suppressed Tg within 1 year from treatment,
TSH stimulated Tg ( by hormone withdrawal or rhTSH)
should be measured 1 year after the ablation to verify
absence of disease. This subset of patients may be
followed up with yearly clinical exam and serum Tg
measurements while on hormone replacement.
Level 3, Category A
Summary of Evidence
Standardization thyroglobulin assays have not yet
been achieved even with the development of an
international standard which is the Certified Reference
Material 457 (CRM -457). A study by Lee, et al.1
compared the concordance of three immunoradiometric
assays (IRMA) to CRM-457, and suggested that
laboratories should adopt IRMAs standardized to CRM
- 457.
In a retrospective analysis of 290 consecutively
diagnosed cases of low risk DTC treated with
thyroidectomy alone and followed up with yearly neck
ultrasound and serum thyroglobulin, final Tg levels were
found to be undetectable (<1 ng/ml) in 274/290 (95%) of
RRA negative patients. This was not significantly
different compared to a matched group of 495 RRA
positive patients who had undetectable levels of Tg in
492 cases (99%) after a median follow up of 5 years. It
was concluded that in most RRA negative patients,
serum thyroglobulin levels spontaneously drop to
undetectable levels within 5-7 years after thyroidectomy.2
Thus, serum thyroglobulin may be useful even in patients
who did not undergo RRA.
Another retrospective study reported on 312
consecutively diagnosed papillary thyroid microcarcinoma
(T1NOMO) patients classified as very low risk (no
family history, no history of head and neck irradiation,
unifocal, no extracapsular extension and classic papillary
Update on Certain Aspects of the EBCPG on Thyroid Nodules
types) who underwent total thyroidectomy, with
radioactive remnant ablation in 44 percent of the subjects.
Yearly follow-up with neck ultrasound and serum
thyroglobulin was done with a median follow up of 6.7
years, which showed that final serum thyroglobulin
levels were undetectable ( < 1 ng/ml) in all patients with
RAI ablation and in 93% of those who did not receive
RAI. The first neck ultrasound (6-12 months after
surgery) and the last sonograms were all negative. The
study proves that strict selection and classification of
patients according to their risk for recurrence could help
guide a cost-effective follow up protocol.3
References
1. Lee JI, Kim JY, Choi JY, et al. Differences in serum thyroglobulin
measurements by 3 commercial immunoradiometric assay kits
and laboratory standardization using Certified Reference Material
457 (CRM-457). Head Neck. 2010; 32(9):1161-6.
2. Durante C, Montesano T, Attard M, et al. On behalf of the PTC
Study Group. Long-term surveillance of papillary thyroid cancer.
Patients who do not undergo postoperative radioiodine remnant
ablation: Is there a role for serum thyroglobulin measurement? J
Clin Endocrinol Metab 2012; 7.
3. Durante C, Attard M, Torlontano M, et al. Papillary Thyroid
Cancer Study Group. Identification and optimal postsurgical
follow-up of patients with very low-risk papillary thyroid
microcarcinomas. J Clin Endocrinol Metab 2010; 95(11): 4882-
8. Epub 2010 Jul 21. PubMed PMID: 20660054.
5.2 What is the role of TSH for postoperative
surveillance in the patient with WDTC?
Serum TSH level monitoring is recommended as
part of postoperative surveillance to determine the
adequacy of suppression to maximize the benefits while
minimizing the risks associated with TSH suppression
therapy.
Level 5, Category A
Summary of Evidence
Thyroid hormone suppression therapy is an essential
part of the postoperative management of patients with
well-differentiated thyroid cancer. The level of
19
suppression following a risk stratified approach may
reduce recurrence and improve thyroid cancer-specific
mortality rates and overall survival rate among high risk
patients. It also has adverse effects on the bone
(osteoporosis) and the heart (arrhythmias). Thus, it is
also important to monitor its levels so as to maximize its
benefits while minimizing treatment related morbidity.
According to the American Thyroid Association
(ATA) and European Thyroid Association ETA), TSH
should be indefinitely maintained at subnormal levels
(<0.1 mU/L) in patients with persistent disease in the
absence of contraindications (cardiac problem or
osteoporosis). In patients initially classified as high risk
but have become clinically and biochemically free of
disease, ATA recommends TSH levels between 0.1-0.5
mU/l for for 5-10 years . For ETA,however, TSH should
be maintained at < 0.1mU/L for 3 -5 years for this
subset of patients to avoid possible recurrence during
this period. Thereafter, TSH may be maintained at low
normal levels ( 0.1 - 0. 5 mU/L ). In patients initially
classified as low risk, serum TSH may be maintained
between 0.1-0.5 mU/L . If they remain disease -free on
follow up, TSH levels may be maintained in the low
normal range (0.3 - 2 mU/L).1,2,3
Biondi, et al. (2010) proposed a stratified approach
in giving TSH suppression therapy according to the risk
of cancer recurrence and progression as well as the risk
of adverse side effects from LT4 therapy with age,
cardiovascular status and skeletal factors taken into
consideration. (See Table 2 under Recommendation
2.6). 3
References
2. Cooper DS, Doherty GM,Haugen BR,et al. Task force on Thyroid
Nodules and Differentiated Thyroid Cancer. Revised American
Thyroid Association management guidelines for patients with
thyroid nodules and differentiated thyroid cancer. The American
Thyroid Association (ATA) Guidelines. Thyroid 2009; 19(11).
2. Pacini F, Castagna MG, Brilli L and Pentheroudakis G. On behalf
of the ESMO Guidelines Working Group Thyroid cancer: ESMO
Clinical Practice Guidelines for diagnosis, treatment and follow-
up. Ann Oncol 2010; 21 (Supplement 5): v214-v9.
3. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus
the risks of adverse effects in differentiated thyroid cancer.
Thyroid 2010; 20(2): 135-46.
20 PJSS Vol. 68, No. 1, January-March, 2013

Appendix A. Oxford centre for evidence-based medicine 2001 levels of evidence.